The transforming growth factor beta (TGFbeta) superfamily is the largest family of secreted proteins in mammals. This family includes the activins, inhibins, TGFbetas, bone morphogenetic proteins (BMPs), and growth differentiation factors (GDFs). These ligands signal through an oligomeric complex of transmembrane type I and type II serine/threonine kinase receptors. Ligand-induced heterodimerization of these receptors leads to phosphorylation of receptor-regulated SMAD proteins, which translocate to the nucleus with the common SMAD4 protein and regulate gene expression. The characterization of mice and humans with mutations in these signaling pathways has revealed the diversity of developmental and physiological processes in which this family functions. Through the support of this grant, my laboratory has generated and analyzed mice with mutations in activin subunits, an activin binding protein (follistatin), activin receptor type II, a downstream receptor binding protein (FKBP 12), and SMADS. We have recently shown that mice with granulosa cell ablation of follistatin are a model for premature ovarian failure in women. The utility of these knockout mice in defining gene function in vivo is unparalleled, and these powerful genetic models have been indispensable for investigating development and reproduction. The overall hypothesis of this R01 renewal is that we will be able to dissect the TGFbeta signaling pathways in the ovary using available and newly-created ovary-specific knockout mouse models. These studies will allow us to place ligands, receptors, and downstream SMAD proteins into biological pathways in a single cell type (i.e., The granulosa cells of the ovary). The Specific Aims of the proposed studies are as follows: 1) Produce transgenic models to define the intraovarian roles of activins; 2) Dissect the activin receptor type II, BMP receptor type II, and BMP receptor type I signaling pathways in the ovary; and 3) Study the interrelationships of the downstream SMAD proteins in ovarian physiology. Generation and characterization of these transgenic mice will define essential and interacting TGFa superfamily signaling components and pathways in the ovary and will continue to be important models for human reproductive diseases including infertility, premature ovarian failure, polycystic ovary syndrome, and ovarian cancer.